Method for producing N-substituted 2-pyrazoline-5-one

ABSTRACT

The present invention relates to a process for preparing N-substituted 2-pyrazolin-5-ones of the formula I                    
     where R has the meaning given in claim 1, which comprises reacting a compound of the formula II                    
     where R, X and Y have the meanings given in claim 1, at elevated temperature with a molar excess of alkali metal hydroxide in an aqueous reaction medium and then adjusting the pH to pH≦6 by adding an acid.

The present invention relates to a process for preparing N-substituted2-pyrazolin-5-ones of the formula I

in which

R is C₁-C₈-alkyl, C₅-C₈-cycloalkyl, phenyl, naphthyl orphenyl-C₁-C₄-alkyl which may be unsubstituted or may carry one or moresubstituents which are inert towards aqueous alkali.

N-Substituted pyrazolinones are useful intermediates for preparingpharmaceuticals and crop protection agents. Thus, for example, U.S. Pat.No. 4,557,753 describes the preparation of benzoyl-substituted5-benzyloxy-1-methylpyrazoles which are prepared starting from1-methylpyrazolin-5-one.

In general, N-substituted pyrazolones are prepared by cyclization ofβ-functionalized acid derivatives with substituted hydrazines. A reviewof various synthesis methods is given in EP-A 240 001. This publicationfurthermore describes a process in which a hydrazone of aβ-hydrazinopropionic acid derivative is cyclized in the presence of abase. In all of the processes mentioned, substituted hydrazines areemployed. Firstly, substituted hydrazines are difficult to obtain andthus expensive. Secondly, substituted hydrazines are usually highlytoxic. Accordingly, it is desirable to prepare N-substitutedpyrazolinones from already known or otherwise obtainable pyrazoleprecursors.

Dorn et al. (J. Pract. Chem. 313 (1971), 115-128) describe a process inwhich 3-pyrazolidone is initially acylated at the 1-nitrogen, thenalkylated with alkyl chlorides or dialkyl sulfates at the 2-nitrogen,followed by removal of the acyl group under oxidizing conditions. Thisgives N-substituted 5-hydroxypyrazoles or their tautomers, i.e.2-pyrazolin-5-ones. However, owing to the large number of reactionsteps, the preparation process is uneconomical. Moreover, dialkylsulfates are highly toxic.

It is an object of the present invention to provide an economicalprocess for preparing the 2-pyrazolin-5-ones of the formula I defined atthe outset, which process uses pyrazoles which are already known oreasily obtainable as starting materials.

We have found that this object is achieved and that compounds of theformula I are obtained in good yields by reacting5-halopyrazole-4-carboxylic acids or derivatives thereof which can behydrolyzed with bases at elevated temperature with aqueous alkali metalhydroxide solutions and then acidifying the reaction mixture.

Accordingly, the present invention relates to a process for preparingN-substituted 2-pyrazolin-5-ones of the formula I defined at the outset,which process comprises reacting a compound of the formula II

in which

X is halogen, and

Y is CN or a group of the formula R′(O)C, in which R′ is a hydroxylgroup or a radical which can be hydrolyzed using alkali metal hydroxide,

and R has the meanings mentioned for formula I,

at elevated temperature with a molar excess of alkali metal hydroxide inan aqueous reaction medium, and then adjusting the pH to pH≦6 by addingan acid.

Hereinbelow, compounds of the formula II where Y=R′(O)C and R′=OH arealso referred to as 5-halopyrazole-4-carboxylic acids, and the compoundswhere Y=CN or Y=R′(O)C where R′≠OH are referred to as5-halopyrazole-4-carboxylic acid derivatives.

The compounds of the formula I are in an equilibrium with the5-hydroxypyrazoles of the formula Ia

Accordingly, the process according to the invention also embraces thepreparation of the compounds Ia.

Organic radicals R′ which can be hydrolyzed under basic reactionconditions, such as alkali metal hydroxide, are known to the personskilled in the art. Examples of suitable radicals R′ are C₁-C₄-alkoxy,such as methoxy, ethoxy, n-propoxy and n-butoxy, which may also besubstituted, and furthermore phenyloxy and benzyloxy, which may also besubstituted at the phenyl ring. Examples of substituents are halogen,such as fluorine, chlorine or bromine, furthermore nitro andC₁-C₄-alkoxy. Further radicals R′ which can be hydrolyzed with base areNH₂ and halogen. Preferred radicals R′ which can be hydrolyzed with baseare C₁-C₄-alkoxy, in particular methoxy and ethoxy. If Y is a group CN,i.e. the compound II is a nitrile derivative, under the reactionconditions of the first step the nitrile group is hydrolyzed to thecarboxyl group. This also applies when Y is R′(O)C and R′ is a groupwhich can be hydrolyzed with alkali metal hydroxide.

Particularly preferred compounds II are the carboxylic acids, i.e. theradical R′ is hydroxyl (═OH). Also preferred are compounds II in which Yis R′(O)C and R′ is C₁-C₄-alkoxy, in particular methoxy or ethoxy.

According to the invention, preferred halogen X is chlorine or bromine,in particular chlorine.

For the reaction according to the invention, the nature of thesubstituent R is of minor importance. The meanings mentioned for R arecollective terms for individual radicals. These meanings are:

C₁-C₈-alkyl: a linear or branched alkyl chain having 1 to 8 carbons, forexample methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl,tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl,1-methylpentyl, 2-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, n-heptyl,n-octyl and 2-ethylhexyl.

C₃-C₈-cycloalkyl: mono- or bicyclic hydrocarbon radicals having 3 to 8carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, norbornyl and 2.2.2-bicyclooctyl.

Phenyl-C₁-C₄-alkyl is a C₁-C₄-alkyl group which is substituted byphenyl, for example benzyl, 1-phenylethyl and 2-phenylethyl.

The abovementioned radicals, and phenyl and naphthyl, may have one ormore substituents which are inert towards aqueous alkali metal hydroxidesolutions. Examples of such radicals are C₁-C₄-alkoxy, such as methoxy,ethoxy, propoxy, n-butoxy, tert-butoxy, furthermore trifluoromethyl,pentafluoroethyl, trifluoromethoxy and pentafluoroethoxy. Anothersuitable alkali-stable substituent for the radicals cycloalkyl, phenyl,naphthyl and phenyl-C₁-C₄-alkyl is C₁-C₄-alkyl. The three last-mentionedsubstituents may also have one or more chlorine or fluorine atoms asalkali-inert substituents at the phenyl group or the naphthyl group.

R is preferably C₁-C₈-alkyl and in particular C₁-C₄-alkyl, which arepreferably unsubstituted, and is particularly preferably methyl orethyl.

The starting materials of the formula II are known to the person skilledin the art and readily obtainable (see EP-A 350176). Compounds of theformula II which are not known can be prepared for example in a simplemanner by oxidation of N-substituted 5-halo-4-methylpyrazoles by theprocess described in EP-A 350 176.

In the process according to the invention, in a first step, a compoundof the formula II is reacted with alkali metal hydroxide in molar excessin an aqueous reaction medium. In the case of the compounds of theformula II, a molar excess of alkali metal hydroxide is ensured whenmore than 2 mol of alkali metal hydroxide are employed per mole of thecompound II. In the first step, one mole is required for exchanging thehalogen X with hydroxyl and one mole is required for hydrolysis orneutralization of the group C(O)R′. According to the invention,preference is given to using 3 to 20 mol of alkali metal hydroxide andin particular 5 to 12 mol of alkali metal hydroxide per mole of thecompound II. Preferred alkali metal hydroxides are sodium hydroxide andpotassium hydroxide, in particular sodium hydroxide.

Suitable aqueous reaction media are both water and mixtures of water andwater-miscible organic solvents. The water-miscible organic solvents arepreferably inert to alkali metal hydroxide under the reactionconditions. Examples of suitable organic solvents are C₁-C₄-alkanols, inparticular methanol and ethanol, and furthermore dimethyl sulfoxide,tetrahydrofuran, dioxane, glycol, glycerol, diethylene glycol,triethylene glycol and the like. In general, the aqueous reaction mediumdoes not contain more than 50% by volume, preferably not more than 30%by volume and in particular not more than 10% by volume of an organicater-miscible solvent. In a preferred embodiment of the presentinvention, water is the only solvent.

The first reaction step is particularly preferably carried out in anaqueous alkali metal hydroxide solution which contains 10 to 50% byweight and in particular 20 to 40% by weight of alkali metal hydroxide.

According to the invention, the first reaction step is carried out atelevated temperature. Elevated temperature is understood as meaningheating at, in general, at least 50° C. and, preferably, at least 90° C.In general, a reaction temperature of 200° C. is not exceeded. Veryparticularly preferably, the reaction is carried out at temperatures inthe range from 120 to 200° C.

Depending on the reaction temperature, the first reaction step iscarried out under atmospheric pressure or under elevated pressure. Atreaction temperatures above 100° C., a reaction pressure of from 1 to 10bar is usually obtained. Typical reaction conditions are, for example inthe case of a purely aqueous reaction medium, 150-1800C and 5-7 bar.

In general, the reaction is carried out until the starting material IIhas been converted virtually completely. Conversion is understood hereas meaning the conversion of the halogen group X in the pyrazole II intoa hydroxyl group or the formation of the corresponding alkoxide and thehydrolysis of the nitrile group (X=CN) or the group —C(O)R′, if R′≠OH.The time required for achieving virtually complete conversion naturallydepends on the chosen reaction conditions and can vary between 0.5 h and24 h. Typical reaction times in purely aqueous systems are generally inthe range from 2 to 10 h.

In the second reaction step, the reaction product obtained in the firstreaction step is reacted under acidic conditions. with evolution of CO₂,the compound I is formed. The evolution of CO₂ is due to the eliminationof the carboxyl group in the 4-position of the pyrazole ring which is,if appropriate, formed by hydrolysis of the group C(O)R′.

The second reaction step is generally carried out without isolating thereaction product formed in the first reaction step. The second reactionstep is preferably initiated by adding an acid to the reaction mixtureof the first reaction mixture. If appropriate, it is also possible toremove some or all of the aqueous solvent of the first reaction stepbefore carrying out the second reaction step and replacing it with a newsolvent, preferably an aqueous solvent and in particular with water.This procedure is suitable in particular when in the first step anorganic solvent has been used which, for example owing to a volatilitywhich is comparable to that of the compound I, or otherwise, makes theisolation of the compound I more difficult.

According to the invention, the second reaction step is carried outunder acidic conditions, i.e. the pH of the reaction mixture in thesecond reaction step is 6 or less and preferably in the range from 1 to3. The pH is preferably not less than 0. The pH is adjusted by adding anacid to the reaction product of the first reaction step. Preferably, theacid is added to the aqueous reaction mixture of the first reactionstep. In general, the reaction mixture of the first reaction step willbe cooled to a temperature suitable for the second reaction step, whichis generally in the range from 0 to 100° C. and preferably in the rangefrom 10 to 50° C., and the acid is then added.

Suitable acids are, in principle, all acids which have an acid strengthwhich is sufficient for achieving the desired pH. If the second reactionstep is carried out directly after the first reaction step, it has to betaken into consideration that excess alkali metal hydroxide has still tobe neutralized. For this reason, a strong acid, preferably a mineralacid, such as hydrochloric acid, sulfuric acid or phosphoric acid, willbe used for adjusting the pH. The acids and in particular phosphoricacid and sulfuric acid are preferably employed in dilute aqueous form.

If the first reaction step is carried out under superatmosphericpressure, it is recommended to vent the reactor prior to neutralisationwith acid. In general, the decarboxylation sets in spontaneously duringthe addition of the acid, when the suitable pH is reached. If desired,the reaction conditions can be maintained for a certain period of time,which can be a few minutes to several hours, in order to bring thedecarboxylation to completion.

The compound I is isolated in a customary manner by work-up of thereaction mixtures of the second reaction step by customary work-upmethods, for example by extractive work-up of the liquid reactionmixture with an organic solvent or by removing the solvent and isolatingthe target compound from the residue obtained. Prior to work-up, it isrecommended to neutralize the reaction mixture of the second reactionstep with a base to a pH≦6, for example pH 6-7. Suitable bases arealkali metal hydroxides, alkali metal carbonates, alkali metalbicarbonates, alkaline earth metal carbonates and alkaline earth metalhydroxides. Usually, alkali metal hydroxides and in particular aqueoussodium hydroxide solution are used for neutralization.

In the process according to the invention, owing to the resulting saltloading, it is frequently advantageous to remove all or some of theaqueous reaction medium of the 2^(nd) reaction step, preferably afterneutralization, by distillation or by evaporation under reducedpressure, and to extract the residue with a suitable organic solvent, toisolate the compound I. Here, the person skilled in the art will choosesolvents in which the desired product is soluble, but not the saltsformed during neutralization. Typical organic solvents for extractionare C₂-C₆-alcohols, such as ethanol, n-propanol, isopropanol, n-butanol,isobutanol, amyl alcohol and isoamyl alcohol, aromatic hydrocarbons,such as toluene, ethylbenzene and xylenes. The target compound I is thenobtained after concentration of the extract to dryness and can bepurified further and worked up in a customary manner.

It is also possible to work up the aqueous reaction medium of the 2^(nd)reaction step, preferably after neutralization, by extraction with apolar solvent which is not or only sparingly miscible with water, forexample by extraction with a C₄-C₆-alcohol, such as n-butanol,isobutanol, amyl alcohol or isoamyl alcohol, or with one of theabovementioned aromatic hydrocarbons. The extraction can be carried outin portions or continuously.

To illustrate the process according to the invention, a typical processprocedure for converting the compounds II into the 2-pyrazolin-5-ones isdescribed below:

The compounds II are dissolved in an aqueous solution of the alkalimetal hydroxide. The concentration of the solution is generally in therange from 10 to 50% by weight and is calculated such that 5-12 mol ofalkali metal hydroxide are present per mole of the compound II. Thissolution is heated in an autoclave at a temperature in the range from150 to 180° C., resulting in a pressure in the range from 5 to 7 bar.The reaction temperature is maintained for 2 to 10 hours. After coolingto room temperature and venting to normal pressure, an amount of mineralacid which is sufficient for adjusting the pH is added. The pH ispreferably in the range from 0 to 6 and in particular in the range from1 to 3. Spontaneous evolution of CO₂ occurs. The mixture is thenneutralized with a base to pH 6-7. The reaction mixture is thenevaporated under reduced pressure to dryness, and the solid residue isextracted, for example in a Soxhlet apparatus, using a suitable solvent.Evaporation of the solvent gives the N-substituted 2-pyrazolin-5-one ofthe formula I in high yield and purity. Instead ofevaporation/extraction, it is also possible to isolate the compound Ifrom the aqueous reaction mixture after neutralization to pH 6-7 byextraction with a suitable solvent, for example isobutanol or toluene.

For further illustration of the invention, examples are given below.

EXAMPLE 1 Preparation of 1-methyl-2-pyrazolin-5-one

In a 250 ml autoclave, 10 g (0.0623 mol) of5-chloro-1-methyl-4-pyrazolecarboxylic acid were dissolved in 100 g of25% by weight strength aqueous sodium hydroxide solution (=0.623 mol).The solution was heated at 175° C. for 6 h. During this time, thepressure increased to 6 bar. After cooling, the autoclave was vented toatmospheric pressure. The reaction mixture was then adjusted to pH 1.5using 60% by weight strength sulfuric acid. This resulted in evolutionof CO₂. After several minutes, the pH was adjusted to 6.5 using 25% byweight strength aqueous sodium hydroxide solution, and the resultingsolution was concentrated under reduced pressure to dryness. The solidresidue was transferred into a Soxhlet apparatus and continuouslyextracted with ethanol. Distillative removal of the ethanol underreduced pressure gave 5.7 g of the target compound of a purity of 98.9%(determined by gas chromatography). The melting point was 113° C. Thiscorresponds to a yield of 92.3% of theory. The product was identified bythe mixed melting point with an authentic sample.

EXAMPLE 2 Preparation of1-ethyl-2-pyrazolin-5-one=5-hydroxy-1-ethylpyrazole

4 g of 5-chloro-1-ethyl-4-pyrazolecarboxylic acid were dissolved in 40 gof 25% by weight strength aqueous sodium hydroxide solution and reactedsimilarly to the procedure described in Example 1. The reactiontemperature of the first reaction step was 170° C., the reactionpressure was 7.5 bar. The duration of the reaction was 8 h. Work-up inthe manner described for Example 1 gave 2.3 g of the target compound ofa purity of 99.7% (determined by gas chromatography). This correspondsto a yield of 89.4% of theory. The melting point was 88° C. The productwas identified by the mixed melting point with an authentic sample.

EXAMPLE 3 Preparation of 1-methyl-2-pyrazolin-5-one, Work-up byLiquid-liquid Extraction

As in Example 1, 10 g of 5-chloro-1-methylpyrazole-4-carboxylic acidwere initially reacted with 100 g of 25% by weight strength aqueoussodium hydroxide solution and then under acidic conditions. The acidicreaction mixture was neutralized to pH 6.5 using 25% by weight strengthaqueous sodium hydroxide solution and the reaction mixture was thentransferred into a liquid-liquid extractor and extracted with isobutanolat the boiling point of the solvent. Isolation of the organic phase anddistillative removal of the isobutanol gave 5.8 g of1-methyl-2-pyrazolinone (purity according to GC: 98.1%). The meltingpoint was 112° C. The yield was 92.5% of theory.

We claim:
 1. A process for preparing N-substituted 2-pyrazolin-5-ones ofthe formula I

in which R is C₁-C₈-alkyl, C₅-C₈-cycloalkyl, phenyl, naphthyl orphenyl-C₁-C₄-alkyl which may be unsubstituted or may carry one or moresubstituents which are inert towards aqueous alkali, which comprisesreacting a compound of the formula II

in which X is halogen, and Y is CN or a group R′(O)C, in which R′ is ahydroxyl group or a radical which can be hydrolyzed using alkali metalhydroxide, and R has the meanings mentioned for formula I, at elevatedtemperature with a molar excess of alkali metal hydroxide in an aqueousreaction medium, and then adjusting the pH to pH≦6 by adding an acid. 2.A process as claimed in claim 1, wherein the compound of the formula IIis reacted with at least 3 mol of alkali metal hydroxide, based on 1 molof the compound II.
 3. A process as claimed in claim 1, wherein thereaction with aqueous alkali metal hydroxide is carried out at atemperature above 90° C.
 4. A process as claimed in claim 1, wherein theacid is added at a temperature in the range from 0 to 100° C.
 5. Aprocess as claimed in claim 1, wherein compounds of the formula II areused in which Y is a group R′(O)C; R′ is C₁-C₄-alkyloxy or OH; X ischlorine or bromine; and R has one of the meanings mentioned for formulaI.
 6. A process as claimed in claim 1, wherein the reaction is carriedout in an aqueous 10-50% by weight strength sodium hydroxide solution.